PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.

Details

Serval ID
serval:BIB_4375000C847C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.
Journal
The lancet. Diabetes & endocrinology
Author(s)
Schmidt A.F., Swerdlow D.I., Holmes M.V., Patel R.S., Fairhurst-Hunter Z., Lyall D.M., Hartwig F.P., Horta B.L., Hyppönen E., Power C., Moldovan M., van Iperen E., Hovingh G.K., Demuth I., Norman K., Steinhagen-Thiessen E., Demuth J., Bertram L., Liu T., Coassin S., Willeit J., Kiechl S., Willeit K., Mason D., Wright J., Morris R., Wanamethee G., Whincup P., Ben-Shlomo Y., McLachlan S., Price J.F., Kivimaki M., Welch C., Sanchez-Galvez A., Marques-Vidal P., Nicolaides A., Panayiotou A.G., Onland-Moret N.C., van der Schouw Y.T., Matullo G., Fiorito G., Guarrera S., Sacerdote C., Wareham N.J., Langenberg C., Scott R., Luan J., Bobak M., Malyutina S., Pająk A., Kubinova R., Tamosiunas A., Pikhart H., Husemoen L.L., Grarup N., Pedersen O., Hansen T., Linneberg A., Simonsen K.S., Cooper J., Humphries S.E., Brilliant M., Kitchner T., Hakonarson H., Carrell D.S., McCarty C.A., Kirchner H.L., Larson E.B., Crosslin D.R., de Andrade M., Roden D.M., Denny J.C., Carty C., Hancock S., Attia J., Holliday E., O'Donnell M., Yusuf S., Chong M., Pare G., van der Harst P., Said M.A., Eppinga R.N., Verweij N., Snieder H., Christen T., Mook-Kanamori D.O., Gustafsson S., Lind L., Ingelsson E., Pazoki R., Franco O., Hofman A., Uitterlinden A., Dehghan A., Teumer A., Baumeister S., Dörr M., Lerch M.M., Völker U., Völzke H., Ward J., Pell J.P., Smith D.J., Meade T., Maitland-van der Zee A.H., Baranova E.V., Young R., Ford I., Campbell A., Padmanabhan S., Bots M.L., Grobbee D.E., Froguel P., Thuillier D., Balkau B., Bonnefond A., Cariou B., Smart M., Bao Y., Kumari M., Mahajan A., Ridker P.M., Chasman D.I., Reiner A.P., Lange L.A., Ritchie M.D., Asselbergs F.W., Casas J.P., Keating B.J., Preiss D., Hingorani A.D., Sattar N.
Working group(s)
LifeLines Cohort study group, UCLEB consortium
ISSN
2213-8595 (Electronic)
ISSN-L
2213-8587
Publication state
Published
Issued date
02/2017
Peer-reviewed
Oui
Volume
5
Number
2
Pages
97-105
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.
In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.
Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m(2), -0·09 to 0·30).
PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.
British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Pubmed
Web of science
Open Access
Yes
Create date
29/09/2017 7:13
Last modification date
30/08/2019 6:26
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